JP6847093B2 - ムスカリン様アゴニスト - Google Patents
ムスカリン様アゴニスト Download PDFInfo
- Publication number
- JP6847093B2 JP6847093B2 JP2018504993A JP2018504993A JP6847093B2 JP 6847093 B2 JP6847093 B2 JP 6847093B2 JP 2018504993 A JP2018504993 A JP 2018504993A JP 2018504993 A JP2018504993 A JP 2018504993A JP 6847093 B2 JP6847093 B2 JP 6847093B2
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- JP
- Japan
- Prior art keywords
- piperidine
- compound according
- hydrogen
- azaspiro
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000000472 muscarinic agonist Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 291
- -1 cyano, hydroxy, methoxy Chemical group 0.000 claims description 84
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 81
- 229910052739 hydrogen Inorganic materials 0.000 claims description 74
- 239000001257 hydrogen Substances 0.000 claims description 73
- 229910052757 nitrogen Inorganic materials 0.000 claims description 62
- 150000003839 salts Chemical class 0.000 claims description 54
- 229910052799 carbon Inorganic materials 0.000 claims description 46
- 229910052760 oxygen Inorganic materials 0.000 claims description 44
- 229910052731 fluorine Inorganic materials 0.000 claims description 42
- 229910052717 sulfur Inorganic materials 0.000 claims description 42
- 239000011737 fluorine Substances 0.000 claims description 41
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 40
- 125000005842 heteroatom Chemical group 0.000 claims description 40
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims description 39
- 125000003118 aryl group Chemical group 0.000 claims description 38
- 125000001153 fluoro group Chemical group F* 0.000 claims description 38
- 238000011282 treatment Methods 0.000 claims description 32
- 239000000460 chlorine Substances 0.000 claims description 30
- 208000010877 cognitive disease Diseases 0.000 claims description 27
- 229920006395 saturated elastomer Polymers 0.000 claims description 27
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 25
- 229910052801 chlorine Inorganic materials 0.000 claims description 25
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
- 125000004432 carbon atom Chemical group C* 0.000 claims description 24
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 21
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 20
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 20
- 229910052794 bromium Inorganic materials 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 230000003551 muscarinic effect Effects 0.000 claims description 20
- 208000024827 Alzheimer disease Diseases 0.000 claims description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- 230000000694 effects Effects 0.000 claims description 16
- 125000004043 oxo group Chemical group O=* 0.000 claims description 16
- KZKRRZFCAYOXQE-UHFFFAOYSA-N 1$l^{2}-azinane Chemical group C1CC[N]CC1 KZKRRZFCAYOXQE-UHFFFAOYSA-N 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 12
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- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- 230000003647 oxidation Effects 0.000 claims description 11
- 238000007254 oxidation reaction Methods 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- 230000001154 acute effect Effects 0.000 claims description 7
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- 150000007942 carboxylates Chemical class 0.000 claims description 6
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- 239000000018 receptor agonist Substances 0.000 claims description 6
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- 206010065390 Inflammatory pain Diseases 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 5
- 230000000926 neurological effect Effects 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 230000001684 chronic effect Effects 0.000 claims description 4
- 230000001149 cognitive effect Effects 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- AQTFKGDWFRRIHR-UHFFFAOYSA-L 3-[18-(2-carboxylatoethyl)-8,13-bis(ethenyl)-3,7,12,17-tetramethylporphyrin-21,24-diid-2-yl]propanoate;cobalt(2+);hydron Chemical compound [Co+2].[N-]1C(C=C2C(=C(C)C(C=C3C(=C(C)C(=C4)[N-]3)C=C)=N2)C=C)=C(C)C(CCC(O)=O)=C1C=C1C(CCC(O)=O)=C(C)C4=N1 AQTFKGDWFRRIHR-UHFFFAOYSA-L 0.000 claims description 2
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- 201000002832 Lewy body dementia Diseases 0.000 claims description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- 125000006260 ethylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 claims description 2
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 13
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 11
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims 1
- ZVYGUQXJVNRSMW-PYUWXLGESA-N ethyl 6-[4-[(2R)-2-ethyl-5-oxopyrrolidin-1-yl]piperidin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate Chemical compound C(C)[C@H]1N(C(CC1)=O)C1CCN(CC1)C1CC2(CN(C2)C(=O)OCC)CC1 ZVYGUQXJVNRSMW-PYUWXLGESA-N 0.000 claims 1
- FBKKBOBKZJREGD-ZYMOGRSISA-N ethyl 6-[4-[(2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl]piperidin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate Chemical compound FC1(C[C@@H](N(C1)C1CCN(CC1)C1CC2(CN(C2)C(=O)OCC)CC1)CO)F FBKKBOBKZJREGD-ZYMOGRSISA-N 0.000 claims 1
- DVZYRUCGRJANBZ-QRWMCTBCSA-N methyl 6-[4-[(2R)-2-(1,3-oxazol-5-yl)pyrrolidin-1-yl]piperidin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate Chemical compound O1C=NC=C1[C@@H]1N(CCC1)C1CCN(CC1)C1CC2(CN(C2)C(=O)OC)CC1 DVZYRUCGRJANBZ-QRWMCTBCSA-N 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 152
- 238000000034 method Methods 0.000 description 78
- 239000002904 solvent Substances 0.000 description 78
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 58
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- 230000002829 reductive effect Effects 0.000 description 51
- 239000000243 solution Substances 0.000 description 46
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 44
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 43
- 239000000203 mixture Substances 0.000 description 43
- 102000005962 receptors Human genes 0.000 description 39
- 108020003175 receptors Proteins 0.000 description 39
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 31
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 31
- 239000000543 intermediate Substances 0.000 description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 29
- 235000019439 ethyl acetate Nutrition 0.000 description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 25
- 239000002253 acid Substances 0.000 description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 25
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 23
- 208000002193 Pain Diseases 0.000 description 22
- 238000004440 column chromatography Methods 0.000 description 22
- 239000010410 layer Substances 0.000 description 22
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 206010012289 Dementia Diseases 0.000 description 17
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- 238000002360 preparation method Methods 0.000 description 17
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- 238000006243 chemical reaction Methods 0.000 description 16
- 239000012071 phase Substances 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 230000003287 optical effect Effects 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 239000000556 agonist Substances 0.000 description 14
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- 208000004296 neuralgia Diseases 0.000 description 14
- 239000012453 solvate Substances 0.000 description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 12
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- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 125000000623 heterocyclic group Chemical group 0.000 description 10
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- 239000004480 active ingredient Substances 0.000 description 7
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 7
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- PEAYUHPVBGYOPD-SECBINFHSA-N tert-butyl (2R)-2-(1,3-oxazol-5-yl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@@H]1c1cnco1 PEAYUHPVBGYOPD-SECBINFHSA-N 0.000 description 1
- NNCPMJHKYIRKSA-SECBINFHSA-N tert-butyl (2r)-2-acetylpyrrolidine-1-carboxylate Chemical compound CC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C NNCPMJHKYIRKSA-SECBINFHSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- 230000001515 vagal effect Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
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- 235000012431 wafers Nutrition 0.000 description 1
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- 238000002424 x-ray crystallography Methods 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical class [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Epidemiology (AREA)
- Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
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| GB1513740.9 | 2015-08-03 | ||
| GBGB1513740.9A GB201513740D0 (en) | 2015-08-03 | 2015-08-03 | Muscarinic agonist |
| PCT/GB2016/052384 WO2017021728A1 (en) | 2015-08-03 | 2016-08-03 | Muscarinic agonists |
Publications (3)
| Publication Number | Publication Date |
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| JP2018522034A JP2018522034A (ja) | 2018-08-09 |
| JP2018522034A5 JP2018522034A5 (enrdf_load_stackoverflow) | 2019-09-12 |
| JP6847093B2 true JP6847093B2 (ja) | 2021-03-24 |
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| JP2018504993A Active JP6847093B2 (ja) | 2015-08-03 | 2016-08-03 | ムスカリン様アゴニスト |
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| JP6083818B2 (ja) | 2011-11-18 | 2017-02-22 | ヘプタレス セラピューティクス リミテッドＨｅｐｔａｒｅｓ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｌｉｍｉｔｅｄ | ムスカリンｍ１受容体アゴニスト |
| GB201404922D0 (en) | 2014-03-19 | 2014-04-30 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| GB201513743D0 (en) | 2015-08-03 | 2015-09-16 | Heptares Therapeutics Ltd | Muscarinic agonists |
| GB201513740D0 (en) * | 2015-08-03 | 2015-09-16 | Heptares Therapeutics Ltd | Muscarinic agonist |
| GB201519352D0 (en) | 2015-11-02 | 2015-12-16 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| TW201726675A (zh) | 2015-12-23 | 2017-08-01 | 默沙東藥廠 | M4毒蕈鹼乙醯膽鹼受體之異位調節劑6,7-二氫-5h-吡咯并[3,4-b]吡啶-5-酮 |
| WO2017107089A1 (en) | 2015-12-23 | 2017-06-29 | Merck Sharp & Dohme Corp. | 3- (1h-pyrazol-4-yl) pyridineallosteric modulators of the m4 muscarinic acetylcholine receptor |
| GB201617454D0 (en) | 2016-10-14 | 2016-11-30 | Heptares Therapeutics Limited | Pharmaceutical compounds |
| WO2018112842A1 (en) | 2016-12-22 | 2018-06-28 | Merck Sharp & Dohme Corp. | 6,6-fused heteroaryl piperidine ether allosteric modulators of m4 muscarinic acetylcholine receptor |
| WO2018112843A1 (en) | 2016-12-22 | 2018-06-28 | Merck Sharp & Dohme Corp. | Heteroaryl piperidine ether allosteric modulators of the m4 muscarinic acetylcholine receptor |
| WO2019126559A1 (en) | 2017-12-20 | 2019-06-27 | Vanderbilt University | Antagonists of the muscarinic acetylcholine receptor m4 |
| TWI801540B (zh) * | 2018-03-23 | 2023-05-11 | 美商輝瑞大藥廠 | 哌嗪氮雜螺衍生物 |
| GB201810239D0 (en) * | 2018-06-22 | 2018-08-08 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| GB201819960D0 (en) | 2018-12-07 | 2019-01-23 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| GB201819961D0 (en) | 2018-12-07 | 2019-01-23 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| GB202020191D0 (en) | 2020-12-18 | 2021-02-03 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| PH12022550713A1 (en) * | 2019-09-25 | 2024-02-12 | Oncoarendi Therapeutics Sa | Process for the production of 5-(4-((2s,5s)-5-(4-chlorobenzyl)-2- methylmorpholino)piperidin-1-yl)-1h-1,2,4-triazol-3-amine |
| CN119390705A (zh) | 2019-10-09 | 2025-02-07 | 诺华股份有限公司 | 作为m4激动剂的5-氧杂-2-氮杂螺[3.4]辛烷衍生物 |
| MX2022004213A (es) * | 2019-10-09 | 2022-05-03 | Novartis Ag | Derivados de 2-azaspiro[3.4]octano como agonistas de m4. |
| US20250064833A1 (en) | 2021-12-13 | 2025-02-27 | Sage Therapeutics, Inc. | Combination of muscarinic receptor positive modulators and nmda positive allosteric modulators |
| WO2025030095A1 (en) * | 2023-08-03 | 2025-02-06 | Neurocrine Biosciences, Inc. | Methods of synthesis |
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| JP2009527568A (ja) | 2006-02-22 | 2009-07-30 | バーテックス ファーマシューティカルズ インコーポレイテッド | ムスカリン受容体の調節剤 |
| WO2007100670A1 (en) | 2006-02-22 | 2007-09-07 | Vertex Pharmaceuticals Incorporated | Spiro condensed piperidnes as modulators of muscarinic receptors |
| JP2012506883A (ja) | 2008-10-29 | 2012-03-22 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | 置換されたスピロアミン |
| FR2945531A1 (fr) | 2009-05-12 | 2010-11-19 | Sanofi Aventis | Derives de 7-aza-spiro°3,5!nonane-7-carboxylates, leur preparation et leur application en therapeutique |
| JP6083818B2 (ja) * | 2011-11-18 | 2017-02-22 | ヘプタレス セラピューティクス リミテッドＨｅｐｔａｒｅｓ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｌｉｍｉｔｅｄ | ムスカリンｍ１受容体アゴニスト |
| WO2014045031A1 (en) * | 2012-09-18 | 2014-03-27 | Heptares Therapeutics Limited | Bicyclic aza compounds as muscarinic m1 receptor agonists |
| CN105189482A (zh) * | 2013-02-07 | 2015-12-23 | 武田药品工业株式会社 | 作为毒蕈碱m4受体激动剂的哌啶-1-基羧酸酯和氮杂卓-1-基羧酸酯 |
| KR102352388B1 (ko) * | 2014-02-06 | 2022-01-17 | 헵테얼즈 테라퓨틱스 리미티드 | 무스카린성 m1 수용체 및/또는 m4 수용체 작용제로서 바이사이클릭 아자 화합물 |
| GB201504675D0 (en) * | 2015-03-19 | 2015-05-06 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| GB201513743D0 (en) | 2015-08-03 | 2015-09-16 | Heptares Therapeutics Ltd | Muscarinic agonists |
| GB201513740D0 (en) * | 2015-08-03 | 2015-09-16 | Heptares Therapeutics Ltd | Muscarinic agonist |
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2015
- 2015-08-03 GB GBGB1513740.9A patent/GB201513740D0/en not_active Ceased
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2016
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- 2016-08-03 WO PCT/GB2016/052384 patent/WO2017021728A1/en active IP Right Grant
- 2016-08-03 US US15/749,743 patent/US10548884B2/en active Active
- 2016-08-03 ES ES16750221T patent/ES2894855T3/es active Active
- 2016-08-03 CN CN201680045225.6A patent/CN107949384B/zh active Active
- 2016-08-03 EP EP16750221.0A patent/EP3331528B1/en active Active
- 2016-08-03 JP JP2018504993A patent/JP6847093B2/ja active Active
- 2016-08-03 CA CA2994143A patent/CA2994143C/en active Active
- 2016-08-03 DK DK16750221.0T patent/DK3331528T3/da active
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2019
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Also Published As
| Publication number | Publication date |
|---|---|
| GB201513740D0 (en) | 2015-09-16 |
| US20180228791A1 (en) | 2018-08-16 |
| US11324738B2 (en) | 2022-05-10 |
| CN107949384A (zh) | 2018-04-20 |
| WO2017021728A9 (en) | 2017-04-27 |
| ES2894855T3 (es) | 2022-02-16 |
| CA2994143C (en) | 2023-09-26 |
| HK1250139A1 (en) | 2018-11-30 |
| CA2994143A1 (en) | 2017-02-09 |
| AU2016302047B2 (en) | 2020-09-10 |
| AU2016302047A1 (en) | 2018-02-15 |
| DK3331528T3 (da) | 2021-10-25 |
| JP2018522034A (ja) | 2018-08-09 |
| EP3331528B1 (en) | 2021-09-29 |
| US10548884B2 (en) | 2020-02-04 |
| EP3331528A1 (en) | 2018-06-13 |
| AU2016302047A8 (en) | 2018-03-08 |
| WO2017021728A1 (en) | 2017-02-09 |
| CN107949384B (zh) | 2025-02-28 |
| US20200129496A1 (en) | 2020-04-30 |
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